Understanding the impact of amino acid mutations on protein-protein binding free energy is fundamental to drug design and functional biology. We propose a novel approach utilizing Protein Large Language Models (PLMs) to characterize both wild-type and mutant proteins, enabling accurate predictions of mutational effects. We employed three state-of-the-art PLMsEsm2, EsmC, and ProtT5to generate sequence-based representations. These representations were subsequently integrated into seven distinct model architectures. Through a rigorous 5-fold cross-validation, we selected the optimal model and feature combination before training on a large-scale data set. Our results show that this PLM-based method significantly outperforms traditional approaches, achieving state-of-the-art (SOTA) predictive performance. The final PPAC model was evaluated on a test set of 9,558 data points and applied to two case studies. The results demonstrate that the model not only provides high-precision predictions but also exhibits a significant advantage in identifying key residues crucial for protein interactions, highlighting its effectiveness in protein interaction modeling.

The development of potent strigolactone (SL) agonists as suicidal germination inducers could be a useful strategy for controlling root parasitic weeds, but uncertainty about the SL perception mechanism impedes real progress. Here we describe small-molecule agonists that efficiently stimulate Phelipanchce aegyptiaca , and Striga hermonthica , germination in concentrations as low as 10 −8 to 10 −17 M. We show that full efficiency of synthetic SL agonists in triggering signaling through the Striga SL receptor, ShHTL7, depends on the receptor-catalyzed hydrolytic reaction of the agonists. Additionally, we reveal that the stereochemistry of synthetic SL analogs affects the hydrolytic ability of ShHTL7 by influencing the probability of the privileged conformations of ShHTL7. Importantly, an alternative ShHTL7-mediated hydrolysis mechanism, proceeding via nucleophilic attack of the NE2 atom of H246 to the 2′C of the D-ring, is reported. Together, our findings provide insight into SL hydrolysis and structure-perception mechanisms, and potent suicide germination stimulants, which would contribute to the elimination of the noxious parasitic weeds.

Natural products (NPs) and their derivatives are important resources for drug discovery. There are many in silico target prediction methods that have been reported, however, very few of them distinguish NPs from synthetic molecules. Considering the fact that NPs and synthetic molecules are very different in many characteristics, it is necessary to build specific target prediction models of NPs. Therefore, we collected the activity data of NPs and their derivatives from the public databases and constructed four datasets, including the NP dataset, the NPs and its first-class derivatives dataset, the NPs and all its derivatives and the ChEMBL26 compounds dataset. Conditions, including activity thresholds and input features, were explored to access the performance of eight machine learning methods of target prediction of NPs, including support vector machines (SVM), extreme gradient boosting, random forests, K-nearest neighbor, naive Bayes, feedforward neural networks (FNN), convolutional neural networks and recurrent neural networks. As a result, the NPs and all their derivatives datasets were selected to build the best NP-specific models. Furthermore, the consensus models, as well as the voting models, were additionally applied to improve the prediction performance. More evaluations were made on the external validation set and the results demonstrated that (1) the NP-specific model performed better on the target prediction of NPs than the traditional models training on the whole compounds of ChEMBL26. (2) The consensus model of FNN + SVM possessed the best overall performance, and the voting model can significantly improve recall and specificity.

Research on direct targets of traditional Chinese medicine (TCM) is the key to study the mechanism and material basis of it, but there is still no effective methods at present. We took Compound Danshen dropping pills (CDDP) as a study case to establish a strategy to identify significant direct targets of TCM. As a result, thirty potential active kinase targets of CDDP were identified. Nine of them had potential dose-dependent effects. In addition, the direct inhibitory effect of CDDP on three kinases, AURKB, MET and PIM1 were observed both on biochemical level and cellular level, which could not only shed light on the mechanisms of action involved in CDDP, but also suggesting the potency of drug repositioning of CDDP. Our results indicated that the research strategy including both in silico models and experimental validation that we built, were relatively efficient and reliable for direct targets identification for TCM prescription, which will help elucidating the mechanisms of TCM and promoting the modernization of TCM.

A key objective for herbicide research is to develop new compounds with improved bioactivity. Protoporphyrinogen IX oxidase (PPO) is an essential target for herbicide discovery. Here, we report using an in silico structure-guided optimization approach of our previous lead compound 1 and designed and synthesized a new series of compounds 2-6. Systematic bioassays led to the discovery of a highly potent compound 6g, 1-methyl-3-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, which exhibited an excellent and wide spectrum of weed control at the rates of 30-75 g ai/ha by the postemergence application and is relatively safe on maize at 75 g ai/ha. Additionally, the Ki value of 6g to Nicotiana tabacum PPO (NtPPO) was found to be 2.5 nM, showing 3-, 12-, and 18-fold higher potency relative to compound 1 (Ki = 7.4 nM), trifludimoxazin (Ki = 31 nM), and flumioxazin (Ki = 46 nM), respectively. Furthermore, molecular simulations further suggested that the thieno[2,3-d]pyrimidine-2,4-dione moiety of 6g could form a more favorable π-π stacking interaction with the Phe392 of NtPPO than the heterocyclic moiety of compound 1. This study provides an effective strategy to obtain enzyme inhibitors with improved performance through molecular simulation and structure-guided optimization.

Strigolactones (SLs) are plant hormones that play various roles in plant physiology, including provoking the germination of parasitic weeds Orobanche and Striga. A family of α/β-hydrolases have been proposed to be the SL receptor proteins. Effective assays for measuring the activity of SL receptors could promote the development of SL-related biology and chemistry. In this study, we developed a new approach called pharmacophore-linked probe virtual screening (PPVS). Its application yielded an effective "off-on" probe named Xilatone Red (XLR). This probe showed a broad spectrum and excellent sensitivity toward SL receptors, including ShD14 (Striga D14), for which the detection limit was determined to be in the micromolar range, outperforming that of the commercial fluorogenic agonist Yoshimulactone Green (YLG). Upon hydrolysis by SL receptors, XLR provided fluorogenic and colorimetric signaling responses. Furthermore, XLR could induce germination of Phelipanche aegyptiaca seeds and prevent Arabidopsis max4-1 branching defects at micromolar concentrations. Our molecular simulations revealed the essential factors in the molecular perception of XLR. We anticipate that this study can prompt the discovery of high-performance SL agonists/antagonists to combat parasitic weeds.

Discovering new protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors is a promising direction for agrochemical research. Herein, we reported the discovery and in silico structure-guided optimization of N-phenyltetrahydroquinazolinones 1 and 2 as new PPO inhibitors. Most of the obtained compounds 1 and 2 exhibited significantly enhanced Nicotiana tabacum PPO (NtPPO) inhibitory potency than that of flumioxazin. Promisingly, 1-(tert-butoxy)-1-oxopropan-2-yl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)benzoate, 2o, with a Ki value of 4 nM, showed ten folds more enhanced NtPPO-inhibiting potency than flumioxazin. Additionally, compounds 2b and 2i showed a broad spectrum of broadleaf weeds control at 37.5-150 g ai/ha, and selective for wheat at 150 g ai/ha in the post-emergent application. The molecular simulation studies revealed the vital basis between N-phenyltetrahydroquinazolinones and NtPPO. The present work indicated that the N-phenyltetrahydroquinazolinone motif might be a potential scaffold for herbicide discovery.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is an effective target for green herbicide discovery. In this work, we reported the unexpected discovery of a novel series of N-phenylaminomethylthioacetylpyrimidine-2,4-diones (2-6) as promising PPO inhibitors based on investigating the reaction intermediates of our initially designed N-phenyluracil thiazolidinone (1). An efficient one-pot procedure that gave 41 target compounds in good to high yields was developed. Systematic Nicotiana tabacum PPO (NtPPO) inhibitory and herbicidal activity evaluations led to identifying some compounds with improved NtPPO inhibition potency than saflufenacil and good post-emergence herbicidal activity at 37.5-150 g of ai/ha. Among these analogues, ethyl 2-((((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)phenyl)amino)methyl)thio)acetate (2c) (Ki = 11 nM), exhibited excellent weed control at 37.5-150 g of ai/ha and was safe for rice at 150 g of ai/ha, indicating that compound 2c has the potential to be developed as a new herbicide for weed management in paddy fields. Additionally, our molecular simulation and metabolism studies showed that the side chains of compound 2c could form a hydrogen-bond-mediated seven-membered ring system; substituting a methyl group at R1 could reinforce the hydrogen bond of the ring system and reduce the metabolic rate of target compounds in planta.

Idiopathic pulmonary fibrosis is a progressive-fibrosing lung disease with high mortality and limited therapy, which characterized by myofibroblasts proliferation and extracellular matrix deposition. Myricetin, a natural flavonoid, has been shown to possess a variety of biological characteristics including anti-inflammatory and anti-tumor. In this study we explored the potential effect and mechanisms of myricetin on pulmonary fibrosis in vivo and vitro. The in vivo studies showed that myricetin effectively alleviated bleomycin (BLM)-induced pulmonary fibrosis. KEGG analysis of RNA-seq data indicated that myricetin could regulate the transforming growth factor (TGF)-β signaling pathway. In vitro studies indicated that myricetin could dose-dependently suppress TGF-β1/Smad signaling and attenuate TGF-β1-induced fibroblast activation and epithelial-mesenchymal transition (EMT). Molecular docking indicated that heat shock protein (HSP) 90β may be a potential target of myricetin, and MST assay demonstrated that the dissociation constant (Kd) of myricetin and HSP90β was 331.59 nM. We demonstrated that myricetin interfered with the binding of HSP90β and TGF-β receptor II and impeded fibroblast activation and EMT. In conclusion, myricetin impedes TGF-β1-induced lung fibroblast activation and EMT via targeting HSP90β and attenuates BLM-induced pulmonary fibrosis in mice.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is an important target for green agrochemical discovery. Herein, a novel N-phenylisoxazoline-thiadiazolo[3,4-a]pyridazine herbicidal active scaffold was designed by the scaffold hybridization strategy. Systematic structural optimization enabled the discovery of a series of derivatives with excellent weed control at 9.375-150 g ai/ha by the post-emergent application. Some derivatives exhibited improved Nicotiana tabacum PPO (NtPPO)-inhibitory activity than fluthiacet-methyl. Of these, 2b, with K-i = 21.8 nM, displayed higher weed control than fluthiacet-methyl at the rate of 12-75 g ai/ha, and selective to maize at 75 g ai/ha. In planta, 2b was converted into a bioactive metabolite S (K-i = 4.6 nM), which exhibited 4.6-fold more potency than 2b in inhibiting the activity of NtPPO. Molecular dynamics simulation explained that 5 formed stronger pi-pi interaction with Phe392 than that of 2b. This work not only provides a promising lead compound for weed control in maize fields but is also helpful to understand the molecular mechanism and basis of the designed hybrids.

In continuation of our search for potent protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) inhibitors, we designed and synthesized a series of novel herbicidal cycloalka[d]quinazoline-2,4-dione-benzoxazinones. The bioassay results of these synthesized compounds indicated that most of the compounds exhibited very strong Nicotiana tabacum PPO (NtPPO) inhibition activity. More than half of the 37 synthesized compounds displayed over 80% control of all three tested broadleaf weeds at 37.5-150 g ai/ha by postemergent application, and a majority of them showed no phytotoxicity toward at least one kind of crop at 150 g ai/ha. Promisingly, 17i (Ki = 6.7 nM) was 6 and 4 times more potent than flumioxazin (Ki = 46 nM) and trifludimoxazin (Ki = 31 nM), respectively. Moreover, 17i displayed excellent, broad-spectrum herbicidal activity, even at levels as low as 37.5 g ai/ha, and it was determined to be safe for wheat at 150 g ai/ha in postemergent application, indicating the great potential for 17i development as a herbicide for weed control in wheat fields.

To better leverage the accumulated bioactivity data in the ChEMBL database, we have developed Bioactivity-explorer, a web application for interactive visualization and exploration of the large-scale bioactivity data in ChEMBL. Mining and integration of the Therapeutic Target Database disease-target mapping into the ChEMBL database has enabled Bioactivity-explorer to include 493,430 scaffolds, 31,400,000 matched molecular pairs, 1330,220 target-target interactions in terms of shared active compounds, 4526,718 target-target interactions in terms of shared active scaffolds, 97,041,700 molecule-molecule interactions and 14,974 disease-target mappings. This web tool is available at http://cadd.pharmacy.nankai.edu.cn/b17r . The source codes of the front end and back end, released under MIT license, can be found at GitHub.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is a promising target for herbicide discovery. Search for new compounds with novel chemotypes is a key objective for agrochemists. Here, we describe the discovery and systematic SAR-based structure optimization of novel N-isoxazolinylphenyltriazinones 5-9 as PPO inhibitors. The in vivo herbicidal activity and in vitro Nicotiana tabacum PPO (NtPPO) inhibitory activity were explored in detail. A number of the new synthetic compounds displayed strong PPO inhibitory activity with Ki values in the nanomolar range. Some compounds exhibited excellent and broad-spectrum weed control at the rate of 9.375-37.5 g ai/ha by postemergence application and showed improved monocotyledonous weed control compared to saflufenacil. Most promisingly, ethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazinan-1-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate, 5a, with a Ki value of 4.9 nM, displayed over 2- and 6-fold higher potency than saflufenacil (Ki = 10 nM) and trifludimoxazin (Ki = 31 nM), respectively. Moreover, 5a showed excellent and broad-spectrum weed control against 32 kinds of weeds at 37.5-75 g ai/ha. Rice exhibited relative tolerance to 5a at 150 g ai/ha by postemergence application, indicating that 5a could be a potential herbicide candidate for weed control in paddy fields.

Color-tunable luminescent supramolecular hydrogel with white-light emission is widely applied in the fields of light-emitting materials and fluorescence sensors due to their good physicochemical and biochemical properties. Using β-cyclodextrin, a class of cyclic oligosaccharide with seven D-glucose units linked by α-1,4-glucose bonds, and laponite as staring materials, we herein developed a photo-luminescent supramolecular hydrogel from laponite and pseudorotaxane that was constructed by the threading of ethylenediamine-modified β-cyclodextrins onto the poly(propylene glycol) bis(2-amionopropylether) (PPG-NH2) chain. The supramolecular hydrogel properties thus obtained were characterized by rheological experiments, zeta potential measurements and scanning electron microscopy (SEM). The results showed that the supramolecular hydrogel possessed satisfactory mechanical properties, negative charges and porous three-dimensional structure. Then, thioflavin T (ThT) and 4-(4-dimethylaminostyryl)-1-methylpyridinium (DASPI), two typical distorted intramolecular charge transfer (TICT) molecules with dramatically increased fluorescence when the molecules are in confined region, were selected as model substrates. Generally, ThT and DASPI had almost no fluorescent emission at an excitation wavelength of 412 nm. By comparing the normalized fluorescence emission spectrum of ThT and the UV-visible absorption spectrum of DASPI, we found that the UV-Vis absorption band of DASPI showed a good overlap with the fluorescence emission band of ThT. Therefore, the fluorescence resonance energy transfer (FRET) process would occur between ThT and DASPI in the laponite/pseudorotaxane supermolecular hydrogel phase, where ThT acted as an energy donor and DASPI acted as an energy receptor. Then the fluorescence behavior of ThT/DASPI pairs in the supramolecular hydrogel phase was investigated. The results showed, after two TICT dyes, ThT and DASPI, were introduced in the hydrogel, the efficient FRET between ThT and DASPI led to the different emission colors including white light through adjusting the ratios of dyes. The convenient preparation and tunable luminescent behaviors of this supramolecular hydrogel will open a new practical path for water-based functional soft materials.

Circularly polarized luminescence (CPL) induced by host-guest complexation remains a challenge in supramolecular chemistry. Herein, a couple of CPL-silent enantiomeric guest binaphthylbis(4,4'-bipyridinium) salts can emit obvious CPL in the presence of cucurbit[8]uril in aqueous media, due to the restriction of molecular rotation limitation effect. Such CPL can be reversibly adjusted by the addition of acid and base. Furthermore, the resultant supramolecular systems can interact with DNA, accompanied by the morphological conversion from branched supramolecular nanowires to exfoliated nanowires, which can enable to the exploration of such supramolecular systems as DNA markers by CPL signals.

Supramolecular hydrogels, which are usually used to develop excellent smart soft materials, are widely applied in miscellaneous fields due to their inherent reversible properties, unique functions and mechanical properties. Compared with covalently linked hydrogels, supramolecular hydrogels have advantages of easy preparation, stimulus responsiveness and good biocompatibility. Herein, after threading amino-modified β-cyclodextrins onto poly(propyleneglycol)bis(2-amionopropylether) (PPG-NH2) chains, the resultant pseudorotaxanes non-covalently interacted with a clay nanosheet (CNS) matrix to construct supramolecular hydrogels bearing negative charges, and the mechanical properties of these hydrogels were positively correlated with the number of amino groups on the pseudorotaxane. Significantly, these hydrogels presented good adsorption properties for cationic dyes. The adsorption capacity (Qe) of the hydrogels towards rhodamine B (RhB), crystal violet (CV), and methylene blue (MB) could reach 181-228 mg g-1, and most of the dyes were adsorbed within 5 min. Thus, these hydrogels may have potential applications in the field of waste water treatment.

A supramolecular nanoparticle that realized the loading and sustained release of ATP was successfully constructed from sulfato-β-cyclodextrin (SCD) and polyethylenimine (PEI). The assembly and disassembly behaviors of supramolecular nanoparticle were investigated by means of Tyndall effect, UV–vis spectroscopy, dynamic light scattering (DLS), zeta potential and transmission electron microscopy (TEM). Significantly, the resulting nanoparticle was disrupted with the increasing of pH and recovered to the spherical nanoparticle as the pH decreased to initial value. Owing to the positive zeta potential, the supramolecular nanoparticle showed the good loading and sustained release abilities towards ATP.

In silico target prediction of compounds plays an important role in drug discovery. The chemical similarity ensemble approach (SEA) is a promising method, which has been successfully applied in many drug-related studies. There are various models available analogous to SEA, because this approach is based on different types of molecular fingerprints. To investigate the influence of training data selection and the complementarity of different models, several SEA models were constructed and tested.